A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer’s Disease Neuropathology

Article type: Research Article

Authors: Alosco, Michael L.^{a; b; 1} | Sugarman, Michael A.^{a; c; 1} | Besser, Lilah M.^d | Tripodis, Yorghos^{a; e} | Martin, Brett^{a; f} | Palmisano, Joseph N.^{a; f} | Kowall, Neil W.^{a; b; g; h} | Au, Rhoda^{b; i; j; k} | Mez, Jesse^{a; b} | DeCarli, Charles^l | Stein, Thor D.^{a; g; m; n} | McKee, Ann C.^{a; b; g; m; n} | Killiany, Ronald J.^{a; k; o; 2} | Stern, Robert A.^{a; b; k; p; 2; *}

Affiliations: [a] Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, USA | [b] Department of Neurology, Boston University School of Medicine, Boston, MA, USA | [c] Department of Neuropsychology, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA | [d] National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA | [e] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [f] Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA | [g] Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA | [h] Neurology Service, VA Boston Healthcare System, Boston, MA, USA | [i] Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, USA | [j] Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA | [k] Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA | [l] Department of Neurology, University of California at Davis Health System, Sacramento, CA, USA | [m] U.S. Department of Veteran Affairs, VA Boston Healthcare System, Boston, MA, USA | [n] Department of Veterans Affairs Medical Center, Bedford, MA, USA | [o] Center for Biomedical Imaging, Boston University School of Medicine, Boston, MA, USA | [p] Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA

Correspondence: [*] Corresponding author: Robert A. Stern, PhD, 72 E. Concord Street, Suite B7800, Boston, MA 02118, USA. Tel.: +1 617 638 5678; Fax: +1 617 638 5679; E-mail: [email protected].

Note: [1] These authors contributed equally to this work as first authors.

Note: [2] These authors contributed equally to this work as senior authors.

Abstract: Background:White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer’s disease. Clinicopathological studies are needed to elucidate and confirm this possibility. Objective:This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer’s disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP. Methods:The sample included 82 participants from the National Alzheimer’s Coordinating Center’s Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Results:60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP–participants (ps < 0.04). Conclusions:This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer’s disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Keywords: Alzheimer’s disease, Alzheimer’s disease neuropathology, cerebrovascular disease, dementia, magnetic resonance imaging, white matter hyperintensities

DOI: 10.3233/JAD-180017

Journal: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1347-1360, 2018